Two-dimensional infrared (2D-IR) spectroscopy is emerging as a powerful new technique for studying the structure and dynamics of biological systems. The strength of this method lies in its ability to measure the coupling between spatially proximal modes of vibration on a picosecond timescale. It is essential that new theoretical tools be developed to connect the experimental measurements with specific molecular structures and motions. These tools will be developed and applied to the interpretation of a series of 2D-IR experiments whose goal to systematically determine the molecular mechanisms of the denaturation of proteins in aqueous urea solutions. The interaction of the amide I vibrational mode of a model compound containing a single peptide bond, N-methylacetamide (MethyI-COHN-Methyl, NMA), with the O-H vibration of water, and the C=O vibration of urea will be simulated with a combined electronic structure/molecular dynamics approach. NMA/water/urea is the simplest system in which the interaction of chemical denaturants and peptide bonds can be studied. The same strategy will be applied to a 21 residue helix forming protein to determine the coupling between the amide I vibrational mode of each residue with the carbonyl stretch of the urea denaturant. The aim is to determine if the urea begins to denature the protein by attacking the interior regions of the helix or at the ends. Determining how denaturants alter the interactions between a protein and water will provide valuable physical insight toward understanding how proteins fold and unfold.